Abstract Alcohol overconsumption and HIV infection are both major health issues worldwide. Alcohol abuse is more prevalent among HIV-infected people than the general population and strongly associated with poor adherence to antiretroviral therapy (ART) and poor treatment response, leading to HIV progression and ART drug resistance. More drastically, alcohol overconsumption and HIV infection independently damage the gastrointestinal (GI) tract mucosal barrier, leading to a leaky gut that allows microbial translocation (MT) and accumulation of microbial components such as lipopolysaccharide (LPS) in the blood. In HIV patients, MT is a cause of chronic immune activation and inflammation, which is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load. We hypothesize that alcohol overconsumption and HIV infection exacerbate MT, immune activation, inflammation, and viral replication, thereby accelerating disease progression of HIV infection and alcoholic liver disease such as alcoholic hepatitis (AH). We also hypothesize that alcohol abstinence slows or reverses immunological and virological impacts in HIV-infected heavy drinkers. We have formed a research team consisting of six scientists with complementary expertise in basic, translational, and clinical research of AH and HIV immunopathogenesis to undertake paradigm-changing investigations in the field of alcohol abuse in HIV patients (Aim 1, UH2 phase). We will enroll HIV-infected heavy drinkers and controls for studying alcohol's impact on HIV-associated comorbidities (Aim 2, UH2 phase). Participants recruited in the UH2 phase will be followed up every 6-month for a year for UH3 phase longitudinal analysis (Aim 3). The UH3 phase will also recruit and follow up new participants to perform a longitudinal analysis of alcohol's impact on MT, immune cell activation, inflammation, and viral replication and integration in HIV-infected heavy drinkers with or without AH (UH3 Phase). Our proposal is highly innovative and will greatly aid in developing novel biomarkers and therapies of HIV-infected heavy drinkers. The biosample repository, upon its placement in the public domain, will become a significant resource for facilitating national and international investigations of alcohol and HIV interactions.